The cellular and molecular mechanisms of peripheral nerve degeneration in human diabetic neurophathy are unknown. Because of the diversity in clinical course and neurologic syndromes, a multitude of factors are likely involved. Efforts to understand the pathogenesis of diabetic neuropathy have concentrated mainly on lesions of the nerve fibers and possible metabolic derangements that might affect neurons and/or Schwann cells. Since microvessel alterations play an important role in the development of diabetic retinopathy and nephropathy, nerve microvessel abnormalities are hypothesized to be involved in the development of neuropathy. This research proposal will focus on 1) human diabetic neuropathy to evaluate a) blood nerve barrier (BNB) alterations of capillary endothelial cells within the endonerium of fascicular sural nerve biopsies from diabetic neuropathy patients versus healthy controls by an evaluation of albumin (Alb), IgG, IgM in both biopsies and plasma after normalization to total endoneurial and plasma protein, respectively, to obtain BNB-Indices for all three proteins; b) possible correlations of the BNB-Indices from diabetic neuropathy patients with clinical measures of neuropathy, pathological abnormalities of nerve fibers and capillaries, and risk factors; c) repeat sural nerve biopsies from patients with diabetic neuropathy after a 12 month interval to determine if the BNB alterations worsen with time; and d) both lysine-bound glucose (furosine) and the advanced glycosylated chromophore on Alb from serum and endoneurium of diabetic neuropathy patients and controls to determine if extensive glycosylation of Alb results in increased permeability within the endoneurium; 2) BNB alterations in experimental animal models of diabetic neuropathy, including the spontaneous diabetic BB-rat, streptozoticin (STZ) diabetes, O2 supplementation of STZ, alloxan diabetes, chronic hypoxic neuropathy, and galactose neuropathy; 3) the specific enzyme marker for capillary endothelial cells, gamma-glutamyl transpeptidase, in sural nerve biopsies and plasma from diabetic neuropathy patients, experimental diabetic animals, and controls to directly assess endoneurial capillary endothelial cell function; and 4) the BNB-Indices for Alb, IgG, and IgM in fascicular sural nerve biopsies from patients with neuropathies other than diabetic neuropathy for BNB alterations of endoneurial capillary endothelial cells. By comparing different human neuropathies and different animal models of neuropathy, it should be possible to further evaluate the BNB alterations observed in human diabetic neuropathy.